在健康的乌干达成年人中分别和同时评估埃博拉病毒和马尔堡病毒糖蛋白 DNA 疫苗的安全性和免疫原性：一项 1b 期、随机、双盲、安慰剂对照的临床试验。
Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1b, randomised, double-blind, placebo-controlled clinical trial.
机构信息
Makerere University Walter Reed Project, Kampala, Uganda.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
出版信息
Lancet. 2015 Apr 18;385(9977):1545-54. doi: 10.1016/S0140-6736(14)62385-0. Epub 2014 Dec 23.
BACKGROUND
Ebola virus and Marburg virus cause serious disease outbreaks with high case fatality rates. We aimed to assess the safety and immunogenicity of two investigational DNA vaccines, one (EBO vaccine) encoding Ebola virus Zaire and Sudan glycoproteins and one (MAR) encoding Marburg virus glycoprotein.
METHODS
RV 247 was a phase 1b, double-blinded, randomised, placebo-controlled clinical trial in Kampala, Uganda to examine the safety and immunogenicity of the EBO and MAR vaccines given individually and concomitantly. Healthy adult volunteers aged 18-50 years were randomly assigned (5:1) to receive three injections of vaccine or placebo at weeks 0, 4, and 8, with vaccine allocations divided equally between three active vaccine groups: EBO vaccine only, MAR vaccine only, and both vaccines. The primary study objective was to investigate the safety and tolerability of the vaccines, as assessed by local and systemic reactogenicity and adverse events. We also assessed immunogenicity on the basis of antibody responses (ELISA) and T-cell responses (ELISpot and intracellular cytokine staining assays) 4 weeks after the third injection. Participants and investigators were masked to group assignment. Analysis was based on the intention-to-treat principle. This trial is registered at ClinicalTrials.gov, number NCT00997607.
FINDINGS
108 participants were enrolled into the study between Nov 2, 2009, and April 15, 2010. All 108 participants received at least one study injection (including 100 who completed the injection schedule) and were included in safety and tolerability analyses; 107 for whom data were available were included in the immunogenicity analyses. Study injections were well tolerated, with no significant differences in local or systemic reactions between groups. The vaccines elicited antibody and T-cell responses specific to the glycoproteins received and we detected no differences between the separate and concomitant use of the two vaccines. 17 of 30 (57%, 95% CI 37-75) participants in the EBO vaccine group had an antibody response to the Ebola Zaire glycoprotein, as did 14 of 30 (47%, 28-66) in the group that received both vaccines. 15 of 30 (50%, 31-69) participants in the EBO vaccine group had an antibody response to the Ebola Sudan glycoprotein, as did 15 of 30 (50%, 31-69) in the group that received both vaccines. Nine of 29 (31%, 15-51) participants in the MAR vaccine groups had an antibody response to the Marburg glycoprotein, as did seven of 30 (23%, 10-42) in the group that received both vaccines. 19 of 30 (63%, 44-80) participants in the EBO vaccine group had a T-cell response to the Ebola Zaire glycoprotein, as did 10 of 30 (33%, 17-53) in the group that received both vaccines. 13 of 30 (43%, 25-63) participants in the EBO vaccine group had a T-cell response to the Ebola Sudan glycoprotein, as did 10 of 30 (33%, 17-53) in the group that received both vaccines. 15 of 29 (52%, 33-71) participants in the MAR vaccine group had a T-cell response to the Marburg glycoprotein, as did 13 of 30 (43%, 25-63) in the group that received both vaccines.
INTERPRETATION
This study is the first Ebola or Marburg vaccine trial done in Africa, and the results show that, given separately or together, both vaccines were well tolerated and elicited antigen-specific humoral and cellular immune responses. These findings have contributed to the accelerated development of more potent Ebola virus vaccines that encode the same wild-type glycoprotein antigens as the EBO vaccine, which are being assessed during the 2014 Ebola virus disease outbreak in west Africa.
FUNDING
US Department of Defense Infectious Disease Clinical Research Program and US National Institutes of Health Intramural Research Program.
背景
埃博拉病毒和马尔堡病毒会引发严重的疾病暴发，病死率很高。本研究旨在评估两种研究性 DNA 疫苗的安全性和免疫原性，一种疫苗（EBO 疫苗）编码扎伊尔和苏丹埃博拉病毒糖蛋白，另一种疫苗（MAR）编码马尔堡病毒糖蛋白。
方法
在乌干达坎帕拉进行的 RV247 是一项 1b 期、双盲、随机、安慰剂对照临床试验，旨在评估单独和同时使用 EBO 和 MAR 疫苗的安全性和免疫原性。18-50 岁的健康成年志愿者按 5:1 的比例随机分配（5:1）接受三种疫苗或安慰剂注射，分别在 0、4 和 8 周进行，疫苗分配在三个活性疫苗组之间平均分配：仅接受 EBO 疫苗、仅接受 MAR 疫苗、以及同时接受两种疫苗。主要研究目的是通过局部和全身反应性和不良事件评估疫苗的安全性和耐受性。我们还根据抗体反应（ELISA）和 T 细胞反应（ELISpot 和细胞内细胞因子染色测定）在第三次注射后 4 周评估免疫原性。参与者和研究者对分组分配情况不知情。分析基于意向治疗原则。这项试验在 ClinicalTrials.gov 注册，编号为 NCT00997607。
结果
2009 年 11 月 2 日至 2010 年 4 月 15 日期间，共纳入 108 名参与者。所有 108 名参与者均至少接受了一次研究性注射（包括 100 名完成注射方案的参与者），并纳入安全性和耐受性分析；107 名有数据的参与者纳入免疫原性分析。研究性注射耐受性良好，各组之间的局部和全身反应无显著差异。疫苗诱导了针对糖蛋白的抗体和 T 细胞反应，我们未检测到两种疫苗单独和同时使用之间的差异。EBO 疫苗组 30 名参与者中的 17 名（57%，95%CI 37-75）对扎伊尔埃博拉病毒糖蛋白有抗体反应，同时接受两种疫苗的 30 名参与者中的 14 名（47%，28-66）有抗体反应。EBO 疫苗组 30 名参与者中的 15 名（50%，31-69）对苏丹埃博拉病毒糖蛋白有抗体反应，同时接受两种疫苗的 30 名参与者中的 15 名（50%，31-69）有抗体反应。MAR 疫苗组 29 名参与者中的 9 名（31%，15-51）对马尔堡病毒糖蛋白有抗体反应，同时接受两种疫苗的 30 名参与者中的 7 名（23%，10-42）有抗体反应。EBO 疫苗组 30 名参与者中的 19 名（63%，44-80）对扎伊尔埃博拉病毒糖蛋白有 T 细胞反应，同时接受两种疫苗的 30 名参与者中的 10 名（33%，17-53）有 T 细胞反应。EBO 疫苗组 30 名参与者中的 13 名（43%，25-63）对苏丹埃博拉病毒糖蛋白有 T 细胞反应，同时接受两种疫苗的 30 名参与者中的 10 名（33%，17-53）有 T 细胞反应。MAR 疫苗组 29 名参与者中的 15 名（52%，33-71）对马尔堡病毒糖蛋白有 T 细胞反应，同时接受两种疫苗的 30 名参与者中的 13 名（43%，25-63）有 T 细胞反应。
解释
本研究是在非洲进行的首次埃博拉或马尔堡病毒疫苗试验，结果表明，两种疫苗单独或联合使用均具有良好的耐受性，并能诱导针对抗原的体液和细胞免疫反应。这些发现为更有效的埃博拉病毒疫苗的加速开发做出了贡献，这些疫苗编码与 EBO 疫苗相同的野生型糖蛋白抗原，目前正在评估中，用于 2014 年西非埃博拉病毒病暴发。
资金
美国国防部传染病临床研究计划和美国国立卫生研究院内部研究计划。
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